Project Summary During the menopause transition, many healthy women with no history of cognitive dysfunction experience subjective difficulties with sustained attention, motivation for work, organization and working memory. Indicators of risk for executive function difficulties at menopause are lacking, as is an understanding of the mechanisms contributing to the unmasking of this vulnerability with loss of estradiol. The overarching purpose of this project is to determine whether early life adversity (adverse childhood experiences; ACE) and insults to the serotonergic system contribute to executive system dysfunction among menopausal women. Multi-modal imaging data from healthy, menopausal women with high and low numbers of adverse childhood experiences who have undergone tryptophan depletion, a paradigm used to lower central serotonin levels, will be used to characterize the effects of adverse childhood experiences and tryptophan depletion on behavioral and brain measures of executive function. I will determine the effect of the adverse childhood experiences and tryptophan depletion on executive performance, activation, and dynamic functional connectivity in menopausal women. Next, I will investigate the role of differences in grey matter volume and resting-state connectivity as explanatory factors underlying differences in executive activation associated with adverse childhood experiences and tryptophan. Then I will determine the role of estradiol in protecting against the effects of tryptophan depletion in women with high and low numbers of adverse childhood experiences. Successful completion of the proposed aims will provide strong support for the mechanisms underlying new-onset cognitive dysfunction during menopause. Given the evidence supporting the early initiation of estrogen therapy in those who are candidates, results of this project have the potential to impact treatment and outcomes applicable to a large portion of the population. !